iTBS and cTBS to an individualized dlPFC target produce differential working memory improvement and session-dependent putamen deactivation

We evaluated the effects of individualized left dorsolateral prefrontal cortex (dlPFC) theta-burst stimulation (TBS) on working memory performance and task-related BOLD activity in 115 healthy adults (iTBS: n = 63; cTBS: n = 52). Stimulation was delivered to an individually-localized left dlPFC target identified using task-based fMRI, with each TBS visit consisting of five 600-pulse trains delivered as either the intermittent (iTBS) or continuous (cTBS) protocol. Participants completed the Sternberg Working Memory paradigm at baseline and approximately 24 hours after each visit.

Groups were well-matched at baseline on all behavioral and neural measures. iTBS produced a significant improvement in working memory accuracy across sessions while cTBS did not, with a significant Group × Session interaction confirming differential trajectories. Both groups showed reaction time speedup across sessions, consistent with a shared practice effect. Despite these behavioral differences, BOLD activity at the dlPFC stimulation site showed no significant effects of Group, Session, or their interaction.

Whole-brain analyses revealed significant session-dependent attenuation of bilateral putamen deactivation during the retention interval in both stimulation groups, with greater putamen deactivation at baseline correlating negatively with working memory accuracy. These results demonstrate that individualized task-based fMRI targeting can link TBS to circuit-level behavioral change, and that downstream subcortical responses may be more sensitive indices of TBS effects than activation at the stimulation site. The absence of a sham condition limits causal inference; observed differences reflect stimulation pattern rather than absolute TBS effects.

The study team would also like to thank the DSMB members who oversaw the project: Dr. Lindsay Oberman (Chair), Dr. This study was made possible with the Center for Advanced Magnetic Resonance Imaging and Spectroscopy (CAMRIS), the radiology research core at the University of Pennsylvania’s Perelman School of Medicine https://www.med.upenn.edu/camris/ and utilized the high-performance computational capabilities of the CUBIC computing cluster at the University of Pennsylvania. (https://www.med.upenn.edu/cbica/cubic.html).

This project was supported by U01 MH130447 (NLB). These authors contributed equally: Ivy Sun, David F. Center for Neuromodulation in Depression and Stress Department of Psychiatry University of Pennsylvania Philadelphia, Philadelphia, PA, USA Ivy Sun, David F.

Gregory, Nusayba Abd-Elmoniem, Milan Patel, Abigail Casalvera, Hannah Gura, Carlos H. Rodriguez, Grant Brighter, Sophia A. Rueda Mora, Sneha Chandrashekar, Walid Makhoul, Desmond J.